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03.04.2019 | Original Article

The granulopoietic cytokine granulocyte colony-stimulating factor (G-CSF) induces pain: analgesia by rutin

verfasst von: Thacyana T. Carvalho, Sandra S. Mizokami, Camila R. Ferraz, Marília F. Manchope, Sergio M. Borghi, Victor Fattori, Cassia Calixto-Campos, Doumit Camilios-Neto, Rubia Casagrande, Waldiceu A. Verri Jr.

Erschienen in: Inflammopharmacology | Ausgabe 6/2019

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Abstract

Rutin is a glycone form of the flavonol quercetin and it reduces inflammatory pain in animal models. Therapy with granulocyte colony-stimulating factor (G-CSF) is known by the pain caused as its main side effect. The effect of rutin and its mechanisms of action were evaluated in a model of hyperalgesia induced by G-CSF in mice. The mechanical hyperalgesia induced by G-CSF was reduced by treatment with rutin in a dose-dependent manner. Treatment with both rutin + morphine or rutin + indomethacin, at doses that are ineffectual per se, significantly reduced the pain caused by G-CSF. The nitric oxide (NO)–cyclic guanosine monophosphate (cGMP)–protein kinase G (PKG)–ATP-sensitive potassium channel (K_ATP) signaling pathway activation is one of the analgesic mechanisms of rutin. Rutin also reduced the pro-hyperalgesic and increased anti-hyperalgesic cytokine production induced by G-CSF. Furthermore, rutin inhibited the activation of the nuclear factor kappa-light-chain enhancer of activated B cells (NFκB), which might explain the inhibition of the cytokine production. Treatment with rutin upregulated the decreased mRNA expression of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) combined with enhancement of the mRNA expression of the Nrf2 downstream target heme oxygenase (HO-1). Intraperitoneal (i.p.) treatment with rutin did not alter the mobilization of neutrophils induced by G-CSF. The analgesia by rutin can be explained by: NO–cGMP–PKG–K_ATP channel signaling activation, inhibition of NFκB and triggering the Nrf2/HO-1 pathway. The present study demonstrates rutin as a promising pharmacological approach to treat the pain induced by G-CSF without impairing its primary therapeutic benefit of mobilizing hematopoietic progenitor cells into the blood.

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Titel: The granulopoietic cytokine granulocyte colony-stimulating factor (G-CSF) induces pain: analgesia by rutin
verfasst von: Thacyana T. Carvalho
Sandra S. Mizokami
Camila R. Ferraz
Marília F. Manchope
Sergio M. Borghi
Victor Fattori
Cassia Calixto-Campos
Doumit Camilios-Neto
Rubia Casagrande
Waldiceu A. Verri Jr.
Publikationsdatum: 03.04.2019
Verlag: Springer International Publishing
Erschienen in: Inflammopharmacology / Ausgabe 6/2019
Print ISSN: 0925-4692
Elektronische ISSN: 1568-5608
DOI: https://doi.org/10.1007/s10787-019-00591-8

Springer Medizin

Abstract

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